Magic Angle Spinning (MAS) is utilized by thousands of Nuclear Magnetic Resonance (NMR) researchers in fields such as macromolecule structure determination, membrane proteins, catalysis, and organo-metallo-complexes. For over three decades, High-Resolution (HR) NMR has been a leading analytical technique for structure and function elucidation of molecules of all types, large and small, in homogeneous systems. More recently, HR-MAS has been used to extend the technique to inhomogeneous systems, such as human and animal tissues. The 1H HR-MAS spectrum of malignant breast cancer tissue shows dramatically increased levels of phosphocholine compared to nonmalignant breast tissue, and it appears likely that many other unambiguous markers can be identified for other pathologies if the signal to noise ratio (SNR) of the HR-MAS probe can be increased sufficiently. HR NMR probes for liquids have become available with cryogenically cooled sample coils that are revolutionizing the field of NMR owing to their factor-of-four improvement in SNR. Even greater improvements in SNR can be achieved with CryoMAS probes of several common types, including 1H/13C/15N and 1H/X. Our work thus far demonstrated about a factor-of-five improvement in SNR in MAS experiments in probes of both of the above types by cryogenically cooling the coils and circuit elements to 25 K while the sample was maintained at room temperature. A substantial additional increase in SNR is expected from a combination of further advances during the Phase II. These advances will include (1) novel coil technology enabling more than a 50% increase in resonator quality factor Q at 25 K in high magnetic fields, (2) refinements in a hermetically sealed spinner design enabling a 25% improvement in magnetic filling factor of the cryocoils, (3) a factor of two increase in the Q of HV ceramic capacitors in the 400-1000 MHz range, and (4) ability to achieve over 75 kHz 1H decoupling field strength in a triple-resonance CryoMAS probe to at least 11.7 T. Substantial improvements in spinning at sample temperatures down to 30 K will also be developed, and provisions for millimeter-wave irradiation will be added to enable Dynamic Nuclear Polarization (DNP) to be easily added. Reducing the sample temperature from 90 K to 40 K in MAS DNP is expected to often in- crease S/N in DNP experiments by an order of magnitude. Additional improvements in S/N will come from further progress in reduction of noise figure (NF) of cryogenically cooled preamps based on the Enhancement mode Pseudomorphic High Electron Mobility Transistors (E-PHEMT). Key Words: solids NMR probes, cryoprobes, HR-MAS, cancer diagnostic tests, molecular structures, cryogenic preamps, dynamic nuclear polarization (DNP) Project Narrative: Nuclear magnetic resonance (NMR) has been one of the most effective analytical tools for determining the structure of complex molecules in biology, chemistry, and medicine, but the NMR technique has had limited success for the very large molecules that are not soluble in suitable liquids. The instrument development proposed herein, called a CryoMAS NMR probe, will reduce the amount of time needed on very expensive NMR spectrometers by a factor of 20 to 100 (from weeks or days to hours or minutes) and thus make it practical to determine the structures of hundreds of thousands of biologically and chemically important macro-molecules for which structures are currently unknown. This is important to drug developments for public health, catalysts, and enzymes, to name but a few. Business/market potential: There are over 5,000 high-field NMR systems installed world-wide, many of which are at research hospitals;and annual NMR equipment sales are currently over $300M. HR-MAS has shown considerable promise for unambiguous diagnostic testing for breast cancer. The proposed MAS probe development would also be of interest to thousands of NMR researchers in chemistry and biochemistry. Market potential of CryoMAS probes over the 15 years following completion of the Phase II almost certainly exceeds $100M and may exceed $300M. PUBLIC HEALTH RELEVANCE: Nuclear magnetic resonance (NMR) has been one of the most effective analytical tools for determining the structure of complex molecules in biology, chemistry, and medicine, but the NMR technique has had limited success for the very large molecules that are not soluble in suitable liquids. The instrument development proposed herein, called a CryoMAS NMR probe, will reduce the amount of time needed on very expensive NMR spectrometers by a factor of 20 to 100 (from weeks or days to hours or minutes) and thus make it practical to determine the structures of hundreds of thousands of biologically and chemically important macro-molecules for which structures are currently unknown. This is important to drug developments for public health, catalysts, and enzymes, to name but a few. Business/market potential: There are over 5,000 high-field NMR systems installed world-wide, many of which are at research hospitals;and annual NMR equipment sales are currently over $300M. HR-MAS has shown considerable promise for unambiguous diagnostic testing for breast cancer. The proposed MAS probe development would also be of interest to thousands of NMR researchers in chemistry and biochemistry. Market potential of CryoMAS probes over the 15 years following completion of the Phase II almost certainly exceeds $100M and may exceed $300M.